Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 2014;25: 666–81.The epithelial–mesenchymal transition (EMT), critical to metastasis, is regulated in part by TGFβ. Yuan and colleagues link long noncoding RNAs (lncRNA) with TGFβ and EMT in hepatocellular carcinoma (HCC) through the microRNA 200 family. Hepatoma cells treated with TGFβ undergo EMT. Microarray analysis identified lncRNA-ATB, validated to have miR-200 binding sites, suggesting a competing endogenous RNA (ceRNA) that competitively binds microRNAs as being activated by TGFβ treatment. Functionally, TGFβ upregulated lncRNA-ATB and downregulated miR-200s, resulting in EMT. In human HCC, elevated levels of lncRNA-ATB were correlated with poor outcome. lncRNA-ATB overexpression promoted metastasis in an animal model, which was partially abrogated by miR-200 inhibition. Overall, the authors found a specific TGFβ-activated lncRNA with effects on miR-200 and subsequent induction of EMT. In addition, they identified a functional interaction with IL11 with activation of STAT3 signaling.Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non–small cell lung cancer. Cancer Discov 2014 Jun;4:662–73.The second-generation ALK inhibitor ceritinib has exhibited early-phase dramatic activity in patients with ALK-rearranged lung cancer. Friboulet and colleagues characterize the activity of ceritinib in crizotinib-resistant models. Ceritinib showed superior activity in models with and without ALK-resistance mutations, suggesting that more potent ALK inhibition with ceritinib abrogates the acquisition of bypass tracks as a mechanism of resistance. Ceritinib effectively inhibited several crizotinib-resistant ALK mutations but was notably ineffective against G1202R and F1174V/C mutations, a finding that can be supported structurally due to steric hindrance and loss in potency of both ceritinib and crizotinib. These studies will be critical for informing the development of next-generation ALK inhibitors.Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014;344:1396–401.Patel and colleagues describe single-cell RNA sequencing (RNA-seq) of 430 tumor cells from five different glioblastoma tumors. All of the tumors were highly heterogeneous, with individual cells corresponding to multiple glioblastoma transcriptional subtypes. All of the tumors had some cells with a proneural subtype regardless of the dominant subtype of the tumor, and stemness signatures were strongest in individual proneural cells. Single-cell real-time PCR in cells from two of the tumors confirmed the presence of multiple subtypes within these tumors. To evaluate relationships between intratumoral heterogeneity and clinical behavior, the authors compared tumors with a low level of heterogeneity (modest signal for nonproneural subtypes) to tumors with a high level of heterogeneity (stronger signals for nonproneural subtypes). Increased heterogeneity was associated with decreased patient survival. These observations indicate that tumors contain multiple cell states with distinct transcriptional programs, linking intratumoral heterogeneity with clinical behavior in glioblastoma.Kong LM, Liao CG, Zhang Y, Xu J, Li Y, Huang W, et al. A regulatory loop involving miR-22, Sp1 and c-Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res; Published OnlineFirst June 6, 2014; doi:10.1158/0008-5472.CAN-13-3555.In their study Kong and colleagues determined the regulatory mechanism of the CD147 (BSG) glycoprotein in breast cancer. Transcription factors Sp1 and MYC regulate the CD147 promoter. miR-22 targeted the 3′UTR of CD147 and repressed CD147 expression. Interestingly, miR-22 also downregulated Sp1 expression, indirectly modulating CD147 expression. Conversely, Sp1 repressed miR-22 transcription by binding to the miR-22 promoter. MYC is also known to inhibit miR-22 expression. Additionally, overexpressing miR-22 decreased breast cancer proliferation, invasion, and metastasis both in vitro and in vivo by targeting CD147. miR-22 itself was downregulated in breast cancer, and its expression was inversely correlated with TNM stage and lymphatic metastasis in patients. Thus, an miR-22/Sp1/MYC network regulates CD147 expression, repressing invasion and metastasis.Franklin RA, Liao W, Sarkar A, Myoungjoo V, Kim MR, et al. The cellular and molecular origin of tumor-associated macrophages. Science 2014;344:921–5Franklin and colleagues reveal that tumor-associated macrophages (TAM) are not mammary gland resident macrophages and do not derive from resident dendritic cells, but rather from inflammatory monocytes. Notch signaling and transcription dependent on RBPJ, a lineage commitment transcription factor, were key components in differentiating TAMs. Importantly, genetic ablation of this subpopulation did not affect the other macrophage subpopulations, but did significantly inhibit mammary tumor growth in the MMTV-PyMT mouse model. This growth suppression was associated with the enrichment of GzmB+ CD8+ T cells at the expense of the PD-1+ subpopulation that is immune tolerant. This study identifies one potential origin of TAMs and their functional role in possibly generating immune tolerance, thus favoring tumor growth.Van Allen EM, Wagle N, Stojanov P, Perrin DL, Cibulskis K, Marlow S, et al. Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine. Nat Med 2014;20:682–8.Van Allen and colleagues generated robust sequencing data from formalin-fixed, paraffin-embedded (FFPE) tumor tissue that were comparable with data from paired frozen tissues, demonstrating similar sequencing metrics. A set of 121 TARGET genes (Tumor Alterations Relevant for GEnomics-driven Therapy) was prioritized. Prior WES data from 511 patients identified 80 somatic alterations in TARGET genes. An independent cohort of 16 patients with a range of cancers showed 41 TARGET alterations, each assigned a level of evidence. Data from a single demonstrative case illustrated potential utility by providing a therapeutic course of action. While WES shows promise clinically, the extensive manual curation and expert opinion required for prioritization, and the need for public databases to share variant data, remain active issues.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.